The overall long-term goal of the proposed research is to design a novel and efficient therapeutic approach for treating advanced hepatocellular carcinoma (HCC). HCC is one of the most common gastrointestinal (GI) malignancies and a major cause of death worldwide, with limited available therapeutic options. Designing safe and efficient therapeutic approaches for treating this disease is thus critically important. Ligand-activated nuclear receptor PPAR? is known to regulate growth and differentiation in a variety of cancer cells, including HCC. In our earlier studies although activation of PPAR? by its ligand Troglitazone (TZD) inhibited HCC cell proliferation, it was unable to induce any apoptosis. The drugs (or combinations) which have the potential of inducing both growth arrest and apoptosis are believed to be most effective in treating advanced forms of cancer. To determine whether TZD can be utilized as a combination therapy instead, we treated HCC cells with TZD in combination with the proapoptotic agent Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Our studies indicated that TRAIL-TZD combination can induce a significant degree of apoptosis in the HCC cells compared to either drug treatment alone and was associated with a dramatic increase in the cleavage of poly (ADP-ribose) polymerase (PARP) and Caspase 3. More in-depth studies were designed to identify the molecular target of this apoptosis, in an effort to improve our understanding of the effectors involved in apoptosis resistance of HCC. These studies revealed that a complete antagonism of ?-catenin pathway is needed to sensitize HCC cells towards TRAIL-TZD-induced apoptosis. Since treatment with TZD alone antagonized ?-catenin pathway at multiple levels via novel mechanisms, and antagonism of ?-catenin promoted HCC cell apoptosis, we hypothesize that PPAR? (or TZD) via antagonizing ?-catenin pathway sensitizes HCC cells towards TRAIL, which are otherwise insensitive to TRAIL alone. The current proposal aims to validate our hypothesis utilizing both in vitro (cellular) and in vivo (xenograft) models while elucidating the mechanisms by which ?-catenin antagonizes apoptosis and PPAR? antagonizes ?-catenin. The following specific aims are proposed to achieve our goals: (1) determine the role of ?-catenin in mediating HCC cell survival and resistance, (2) determine the mechanism by which ?-catenin is modulated during apoptosis and survival of HCC and (3) determine the role of ?-catenin on HCC survival and resistance in vivo. Successful completion of the studies is expected to provide important preclinical data on the efficacy of TRAIL-TZD combination on HCC cell apoptosis and a fundamental understanding whether ?-catenin serves as a molecular target to mediate apoptotic resistance. Based on these and as part of our long-term goal, more specific next generation inhibitors of ?-catenin (with less collateral toxicity) can be designed to be utilized i combination therapies for effectively treating patients with advanced forms of HCC.